A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a vitally encoded protease to generate mature vital proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E., et. al., Proc. Natl. Acad. Sci. USA, 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results suggest that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame Ratner, L. et al., Nature, 313, 277(1985)!. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature 329,351 (1987)!. Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.
Related art includes Hoffman-LaRoche EPO applications. EPO 389898, EPO 346847, and EPO 432695 each disclose HIV protease inhibitors but the compounds are very different because they have an amino acid (or analog thereof) attached to the amino-terminal end of the transition state analog. EPO 432694 discloses synthetic intermediates which are different from the compounds of the present invention.
The particular advantages of the compounds of the present invention are increased oral bioavailability and lower serum protein binding.